The present invention relates to inhibition of growth factor tyrosine kinase receptor activity, particularly inhibition of angiogenesis and related disorders, tumor progression and growth factor related skeletal disorders, by porphyrin and corrole compounds, and to certain novel porphyrin compounds.
ABBREVIATIONS: AP, alkaline phosphalase; EGF, epidermal growth factor; bFGF, basic fibroblast growth factor; FGF, fibroblast growth factor, FGFR, FGF receptor, FGFR-1, FGF receptor-1; FGFR-3, FGF receptor-3; UP, FGFR-1-alkaline phosphatase fusion protein; FR3-AP, FGFR-3-alkaline phosphatase fusion protein; HB-EGF, heparin-binding EGF-like growth factor; HGF, hepatocyte growth factor, HSPG, heparan sulfate proteoglycans; IGF, insulin-like growth factor, LLC, Lewis Lung Carcinoma; NGF, nerve growth factor, PDGF, plateleterived growth factor; SMC, smooth muscle cells; TKR, tyrosine kinase receptor; VEGF, vascular endothelial growth factor, VSMC, vascular smooth muscle cells.
Growth factors play a pivotal role in the multistep pathway of cell differentiation and migration, tumor and metastasis progression, and angiogenesis.
The pathological mechanism of many proliferative diseases is determined by biological events such as growth factor receptor stimulation, autophosphorylation, and the phosphorylation of intracellular protein substrates.
Phosphorylation of tyrosine residues on protein substrates in normal cells serves a critical function in intracellular growth signaling pathways initiated by stimulated extracellular growth factor receptors. Growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), vascular endotheial growth factor (VEGF) and hepatocyte growth factor (HGF), associate with their respective extracellular receptors thus activating the intracellular tyrosine kinase domains of said receptors and catalyzing the phosphorylation of the receptors themselves (autophosphorylation) or of intracellular substrates. This association between the growth factor ligand and the respective receptor simulates tyrosine kinase activity as one of the initial biochemical events leading to DNA synthesis and cell division Therefore, compounds which inhibit protein tyrosine kinases associated with intracellular growth factor signal transduction pathways may be useful for the treatment of cellular proliferative disorders.
Fibroblast growth factors (FGFs) are abundant m normal and malignantly transformed cells and play a pivotal role in the multistep pathway of malignant transformation, tumor progression, metastasis and angiogenesis. In adults, bFGF, as well as the FGF oncogenes HST (FGF4) and int-2 (FGF-3) are found in tumors such as stomach cancer, Kaposi""s sarcoma, melanoma and breast cancer.
FGFs bind avidly to the glycosaminoglycan heparin and to heparan sulfate proteoglycans (HSPG) found on cells and in the extracellular matrix. Studies on the mode of action of FGFs identified a novel role for beparin-like molecules in the formation of distinct FGF-heparin complexes that are essential for binding of FGF to its cognate receptor (Yayon et al, 1991; Rapraeger et al, 1991). We and others have recently addressed the importance of specific heparin and heparan sulfate structures in FGF receptor binding activity (Guimond et al, 1993; Aviezer et al, 1994a) and have demonstrated that specific HSPGs such as perlecan, function as a low affinity, accessory receptor for bFGF and as a potent angiogenic modulator (Aviezer et al, 1994b).
FGF receptors were found to play a role in genetically acquired growth disorders. Thus, a number of mutations in FGF receptors have been implicated in various forms of human skeletal dysplasias. For instance, achondroplasia, the most common form of human dwarfism, is caused by a pecfic mutation in the transmembrane domain of FGFR-3 (Rousseau et al, 1994; Shiang et al, 1994). Other skeletal disorders such as Crouzon""s syndrome and thanatophoric dysplasia, involve mutations in the extracellular domain (Reardon et al, 1994) or the kinase domain of FGF receptors. In achondroplasia, a point mutation (Gly-380/Arg) in the transmembrane domain of FGFR-3 leads to impaired growth. Since we have identified FGF-9 as a putative ligand for FGFR-3 (Hecht et al, 1995), it is conceivable that strategies aimed at check points along the biochemical mechanism of the FGFR-3 activation pathway, may result in treatment of achondroplasia Naski et al, 1996, have demonstrated that both the achondroplasia and thanatophoric dysplasia mutations constitutively activate the receptor as evidenced by receptor tyrosine phosphorylation. These findings have been biologically supported by knock out of the FGFR-3 gene (Deng et al, 1996). Furthermore, it seems that FGFRs are involved in bone and cartilage benign tumors, such as hereditary multiple exostosis, osteoarthritis and others. Exostosis is an osteocartilaginous benign tumor of an autosomal dominance, diversed phenotype and heterogeneous genetics characterized by the formation of cartilaginous capped metaphyseal bony protrusions.
Vascular endothelial growth factor (VEGF) is a known endothelial mitogen and a potent enhancer of vascular permeability. VEGF is a multifunctional cytoline that exerts in vivo a key role in physiological and pathological neoangiogenesis by stimulating endothelial cell proliferation and vessel hyperpermeability, VEGF exists as one of four different isoforms, respectively, VEGF 121, VEGF 165, VBGF 199, and VEGF 206. VEGF121 does not bind heparin while the other three isoforms do, and it has been documented that the binding of VEGF165 to its receptor is dependent upon cell surface heparin suite proteoglycans (Gitay-Goren et al, 1992). VEGF binds to Fit-1 and Flk-1/KDR cell membrane receptors which are members of the tyrosine kinase receptor family. VEGF seems to be a crucial mediator of physiological neoangiogenesis during the embryonic development and the female cycle.
VEGF also has a major role in the pathogenesis of many diseases including hypervascularized tumors, rheumatoid arthritis, cutaneous diseases and proliferative retinopathies. VEGF gene expression in vitro is enhanced approximately ten times by hypoxia. Current evidence (Patt et al, 1998) suggests that hypoxia is also the driving force for VEGF gene expression in cells in vivo and represents the most important trigger for tumor angiogenesis and edema. Recent approaches to inhibit tumor angiogenesis and metastasis formation concentrate on the disruption of VEGF/VEGF receptor signal transduction pathway in vivo. Persistent angiogenesis may cause or exacerbate certain diseases such as psoriasis, rheumatoid arthritis, hemangiomas, angiofibromas, diabetic retinopathy and neovascular glaucoma. An inhibitor of VEGF activity would be useful as a treatment for such diseases and other VEGF-induced pathological angiogenesis and vascular permeability conditions, such as tumor vascularization.
The EGF receptor, which main ligands are EGF, HB-EGF and transforming growth factor xcex1 (TGF-xcex1), is involved in the disease processes of many malignant tumors, especially colon and breast cancers. Overexpression and mutation of the closely related Erb-2 and Erb-3 receptors have been shown to be the major risk factors in poor prognosis of breast cancer. HB-EGF is a most potent activator of the EGF receptor on smooth muscle cells (SMC), including VSMC, playing a crucial role in the pathogenesis of atherosclerosis and benign hypertrophy of the uterus and the formation of leiomyomas (tumors composed of nonstriated muscular tissue).
PDGF has been identified as a potent endogenous vascular smooth muscle cells (VSMC) mitogen and chemoattractant. Proliferation and directed migration of VSMC are important elements in processes such as vascular remodeling, atherosclerosis and restenosis. In balloon-injured rat model, elevated vascular mRNA expression of PDGF A and B chains and PDGF receptors has been observed in carotid arteries (J. Cell Biology, 1990, 111: 2149-2158) and infusion of PDGF greatly increased intimal thickening and migration of VSMC (J. Clin. Invest. 1992, 89: 507-511).
Hepatocyte growth factor (HGF), also known as scatter factor (SF), is the prototype of a family of structurally related soluble molecules (scatter factors), which also includes the HGF-lik/macrophage-stimulating protein (HGF1/MSP). HGF and HGF1/MSP control a complex genetic program known as xe2x80x98invasive growthxe2x80x99 which leads to cell dissociation, proliferation, invasion of extracellular matrix, prevention of apoptosis, acquisition of polarity and tubule formation. HGF is synthesized by mesenchymal cells and is a paracrine effector of cells, predominantly epithelial, that express the Met tyrosine kinase receptor. The HGF and HGF1/MSP receptors are the tyrosine kinases encoded by the homologous genes met and ron. During development, coordinated control of invasive growth by HGF-Met is essential. Met and Ron receptor signalling occurs via a two-phosphotyrosine multifunctional docking site located in their C-terminal regions.
HGF is a pleiotropic cytokine known to be involved in tissue regeneration and repair (Van de Woude et al, 1997). HGF exerts mitogenic and motogenic effects in different cell types. One of the mechanisms by which HGF exerts its antiproliferative effect is induction of apoptosis. HGF activation of Ras and phosphantidylinositol-3-kinase through the multifunctional docking site is required for receptor-mediated invasive growth. In a number of malignant tumours met and ron are mutated, amplified or overexpressed. Oncogenically activated met and ron confer transforming, invasive and metastatic properties to normal cells. Point mutations of the multifunctional docking site dissociate the transforming potential from the invasive-metastatic phenotype showing that distinct signalling pathways are involved. An increasing number of reports have implicated Met-HGF signalling in a variety of human cancers (Yanagawa et al, 1998).
Nerve growth factor (NGF) was characterized over 4 decades ago, and like the other neurotrophins subsequently discovered it is best known for its trophic role, including the prevention of programmed cell death in specific populations of neurons in the peripheral nervous system. This property can be accounted for by the activation of a tyrosine kinase receptor. NGF also regulates neuronal function, as illustrated by its role in pain and inflammation, and in synaptic plasticity. Numerous studies published in the last 10-15 years have shown that NGF, a polypeptide originally discovered in connection with its neurotrophic activity, also acts on cells of the immune system Finally, NGF recently was shown (Frade and Barde, 1998) to activate the neurotrophin receptor p75 (p75M), a receptor with no intrinsic catalytic activity and with similarities to members of the tumor necrosis factor receptor family. During normal development, the activation of p75NTR by NGF actually kills cells in the central nervous system (Frade and Barde, 1998). One remarkable property of NGF is then that it controls cell numbers in opposite ways in the developing nervous system, a result of its unique ability to activate two different receptor types. NGF has been found in various immune organs including the spleen, lymph nodes and thymus, and cells such as mast cells, eosinophils, and B and T cells (Aloe et al, 1997).
The circulating levels of NGF increase in inflammatory responses, in various autoimmune diseases, in parasitic infections, and in allergic diseases. Stress-related events both in animal models and in man also result in an increase of NGF, suggesting that this molecule is involved in neuroendocrine functions (Connor et al, 1998). The rapid release of NGF is part of an alerting signal in response to either psychologically stressful or anxiogenic conditions in response to homeostatic alteration. Thus, the inflammation and stess-induced increase in NGF might alone or in association with other biologic mediators induce the activation of immune cells during immunologic insults. Recent evidence suggests that neurotrophic factors that promote the survival or differentiation of developing neurons may also protect mature neurons from neuronal atrophy in the degenerating human brain. Furthermore, it has been proposed that the pathogenesis of human neurodegenerative disorders may be due to an alteration in neurotrophic factor and/or trk receptor levels. The use of neurotrophic factors as therapeutic agents is a novel approach aimed at restoring and maintaining neuronal function in the central nervous system (CNS).
Porphyrins have been of interest of chemists and medical scientists for over a century. It has been known for many years that porphyrins interact with neoplastic tumors and the fact that porphyrins demonstrate high affinity to tumorigenic cells in vitro and solid tumors in vivo, is well established (Dougherty et al, 1998: Jori et al, 1986).
Porphyrin derivatives have been disclosed for the treatment of tumors, cancers and malignant tissues in combination with electromagnetic radiation or radioactive emissions. Since they absorb light strongly in the 690-880 nm region, many porphyrins were suggested for use as photosensitizers in photodynamic therapy (PDT). See, for example, U.S. Pat. Nos. 5,268,371 and 5,272,142, European Patent Nos. 213272 and 584552 and Jori et al. (1986).
Some porphyrin derivatives have been disclosed for use in combination with electromagnetic radiation or radioactive emissions for inhibiting angiogenesis. See, for example, the PCT publications WO 95/24930, WO 94/12239 and WO 93/02192 and U.S. Pat. Nos. 5,576,013 and 5,284,647. Some publications suggested the use of porphyrin derivatives as anti-tumor agents in the absence of electromagnetic radiation or radioactive emission based on their ability to cleave DNA (U.S. Pat. No. 4,658,023 and U.S. Pat. No. 5,236,914). The porphyrins disclosed in U.S. Pat. No. 5,236,914 always include a central Fe or Mn metal atom and may be substituted by 1 to 3 positively charged N-alkyl-pyridylium groups.
Corroles are slightly contracted porphyrins. The corroles are much less known than porphyrins and their synthesis is very complex. The first corrole was reported in 1965. A simple procedure for corrole synthesis is the subject of Israel Patent Application No. 126426. Neither this patent application nor any other publication disclose or suggest any pharmaceutical application of corroles.
None of the foregoing references teach or suggest that the porphyrin and corrole compounds of the compositions of the present invention inhibit growth factor receptor tyrosine kinase (RTK) activity.
It has now been found, according to the present invention, that certain porphyrin and corrole compounds can inhibit growth factor receptor tyrosine kinase (RTK) activity.
The present invention thus relates, in one aspect, to a pharmaceutical composition for inhibiting growth factor receptor tyrosine kinase (RTK) activity comprising a tetrapyrrolic macrocycle selected from a. 5,10,15,20-tetraaryl-porphyrin and a 5,10,15-triaryl-corrole, wherein said aryl radical is a carboaryl, a heteroaryl or a mixed carboaryl-heteroaryl radical and at least two of said aryl radicals are positively charged, and a pharmaceutically acceptable carrier.
The growth factor RTK whose activity is inhibited by the compositions of the invention may be fibroblast growth factor (FGF) RTK, epidermal growth factor (EGF) RTK, heparin-binding EGF-like growth factor (HB-EGF) RTK, platelet-derived growth factor (PDGF) RTK, vascular endothelial growth factor (VEGF) RTK, nerve growth factor (VGF) RTK, hepatocyte growth factor (HGF) RTK, insulin RTK and insulin-like growth factor (IGF) RTK.
All fibroblast growth factor receptors are encompassed by the invention but particularly FGFR-1 and FGFR-3 are envisaged, which ligands are, among others, bFGF and FGF9, respectively.
In one aspect, the pharmaceutical compositions of the invention are used for inhibition of cell proliferation mediated by growth factor RTK activity. In one embodiment of this aspect, the compositions are used for inhibition of angiogenesis or neovascularization by particularly inhibiting the binding of VEGF to a VEGF receptor. The treatment of a condition characterized by excess of undesired angiogenesis with such a composition is not accompanied by any added electromagnetic radiation having a frequency absorbed by the porphyrin or corrole derivative or any radioactive emissions from said derivatives. Preferred compounds according to the invention for treatment of angiogenesis are the porphyrin herein designated P1 and the corrole herein designated P21.
In another embodiment of this aspect, the compositions are used for inhibition of vascular smooth muscle cell proliferation in disorders including atherosclerosis, hyperthrophic heart failure and postsurgical restenosis.
Restenosis after successful percutaneous transluminal coronar angioplasty (PTCA) remains a major problem despite great improvement in the technique, use of certain drugs and stents implantation. Heparin-binding growth factors (HBGF), mainly the FGFs and HB-EGF, play a crucial role in the pathogenesis of restenosis by enhancing medial smooth muscle cells (SMC) migration and proliferation and subsequently neo-intima formation The FGF antagonists comprised in the compositions of the present invention interfere with the interaction between HBGF and their receptors and exert a marked inhibitory effect on SMC proliferation as shown by direct cell proliferation assays and reduced thymidine incorporation, as well as by direct inhibition of high affinity basic FGF in vitro and on cells. The inhibitors block ligand-receptor interaction by competitively inhibiting the essential association between both ligand and receptor with heparan sulfates and in a dose-dependent manner. According to the invention, porphyrin compounds P1 and P20 were found particularly active in the prevention of restenosis after PTCA by specifically inhibiting SMC proliferation and luminal narrowing by the neo-intima.
In another embodiment of this aspect, the compositions of the invention are used for inhibition of cell proliferation and migration in the treatment of primary tumors and metastasis. The inhibition of tumor growth and metastasis, processes in which bFGF appears to play a pivotal role, was tested both in vitro and in vivo with the porphyrins and corroles. A clear inhibition of primary tumor formation in nude mice model and of primary tumor growth and metastasis in C57 black mice injected with LLC could be observed, particularly with the compounds herein designated P1, P5, P7, P20 and P21.
In another embodiments of this aspect, the compositions of the invention are used for treatment of nonmalignant tumors such as benign prostate hyperthrophy, diabetic retinopathy, psoriasis, rheumatoid arthritis, and other disorders including retrolental fibroplasia, macular degeneration, hemangioma, arteriovenous malformation, hypertrophic scars, acne, scleroderma and autoimmune diseases.
In another aspect, the pharmaceutical compositions of the invention are used for treatment of bone and cartilage related disorders including inherited skeletal disorders such as achondroplasia, dwarfism, craniosyuostosis. According to the invention, the compounds, and particularly the porphyrin herein designated P16, were found to inhibit the binding of FGF9 to FGFR-3, indicating that they can be useful for treating FGFR-3 related growth disorders such as achondroplasia
The pharmaceutical composition of the invention comprises particularly a 5,10,15,20-tetaaryl-porphyrin of the formula: 
wherein Ar1, Ar2, Ar3, and Ar4, the same or different, are each an aryl radical selected from a carboaryl, a heteroaryl and a mixed carboaryl-heteroaryl radical, at least two of said aryl radicals being positively charged, n is an integer from 2 to 4 and X is a pharmaceutically acceptable anion, or
a 5,10,15-triaryl-corrole of the formula: 
wherein Ar1, Ar2, and Ar3, the same or different, are each an aryl radical selected from a carboaryl, a heteroaryl and a mixed carboaryl-heteroaryl radical, at least two of said aryl radicals being positively charged, n is an integer from 2 to 3 and X is a pharmaceutically acceptable anion.
As defined herein, the carboaryl radical, by itself or as part of the mixed carboaryl-heteroaryl radical, is a substituted monocyclic or bicyclic aromatic radical and the heteroaryl radical, by itself or as part of the mixed carboaryl-heteroaryl radical, is a substituted 5-6 membered aromatic ring containing 1-3 heteroatoms selected from O, S and/or N.
The carboaryl radical may be phenyl, biphenyl or naphthyl substituted by one or more radicals including, but not being limited to, halogen, alkyl, alkoxy, alkylamino, aminoalkylamino, and trialkylammonium, wherein the alkyl radical may have from 1 to 8, preferably 1-4, carbon atoms. The halogen may be chloro or, preferably, fluor. The carboaryl radical may be a phenyl radical substituted by fluoro such as, for example, pentafluorophenyl, or by tri(C1-C8)alkylammonium, for example, 4trimethylammoniophenyl, or it may have different substituents, for example, amino(C1-C8)alkylamino-tetrafluorophenyl, e.g. aminopropylamino-2,3,5,6 -tetrafluorophenyl, or tri(C1-C8)alkylammonium-tetrafuorophenyl, for example, 4trimethylammoniophenyl-2,3,5,6-tetrafluorophenyl.
The heteroaryl radical may be a 5-6 membered aromatic ring containing 1-3 heteroatoms selected from O, S and/or N including, but not being limited to, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl and triazinyl, substituted by one or more radicals including, but not being limited to, halogen, alkyl, alkoxy, alkylamino, aminoalkylamino, and trilkylammonium. Examples of such heteroaryl radicals are N-(C1-C8)alkyl-pyridylium, preferably 2-; 3- or 4-(N-methyl) pyridylium.
An example of a mixed carboaryl-heteroaryl radical according to the invention is N-(Cl-Cg)alkyl-pyridylium-tetrafluorophenyl, for example, 4-N-methyl-2-pyridylium)-2,3,5,6-tetrafluoro-phenyl and the corresponding 3- and 4-(N-methyl) pyridylium compounds.
The anion Xxe2x88x92 according to the invention is a halide, preferably Ixe2x88x92, or a pseudo halide anion, or the anion of a carboxylic or sulfonic acid, for example from alkyl sulfonate, trifluoromethyl sulfonate or tosyl (p-toluene sulfonic acid).
Some of the porphyrins used in the present invention are known and either are commercially available or can be prepared by known procedures. P1-P5, for example, are commercially available, and P15, for example, can be prepared according to La et al, 1999.
In another aspect, the invention relates to novel 5,10,15,20-tetraaryl-porphyrins of the formula: 
wherein Ar1, Ar2, Ar3, and Ar4, the same or different, are each an aryl radical selected from a carboaryl, a heteroaryl and a mixed carboaryl-heteroaryl radical, at least two of said aryl radicals being positively charged, n is an integer from 2 to 4 and X is a pharmaceutically acceptable anion, and wherein at least one of the non-positively charged aryl radicals, if present, is pentafluorophenyl or 4-amino(C1-C8)alkylamino-2,3,5,6-tetrafluorophenyl, and at least two of the positively charged aryl radicals are N-(C1-C8)alkyl-pyridylium or 4-N(C1-C8)alkyl-pyridylium-2,3,5,6-tetrafluorophenyl, particularly 4-(N-methyl-2-pyridylium)-2,3,5,6-tetrafluoro-phenyl, 4-(N-methyl-3-pyridylium)-2,3,5,6-tetrafluoro-phenyl or 4-(N-methyl-4-pyridylium)-2,3,5,6-tetrafluoro-phenyl.
The novel porphyrins of the invention include the compounds herein designated P16, P17, P18, P19 and P20, which formulas appear in Appendix A.
The novel porphyrins according to the invention corresponding to the general formula II: 
in which Ar represents: 
wherein the nitrogen atom (and the positive charge) is located at either the 2-, or 3-, or 4 position, and R represents C1-C8 linear or branched alkyl and Xxe2x88x92 represents a halide or pseudohalide anion, or the anion of a carboxylic of sulfonic acid, are prepared by a three-step method comprising:
a) condensation of pyrrole with a mixture of pentafluorobenzaldehyde and either 2-, or 3-, or 4-pyridinecarboxaldehyde in an acidic medium, such as to obtain a mixture of all possible substituted precursors in which the nitrogen atoms are tertiary and free of positive charges;
b) chromatographic separation of the above mentioned precursors by liquid chromatography. The relative amounts of each precursor are controlled in step (a), by adjusting the ratio of the appropriate pyridinecarboxaldehyde and pentafluorobenzaldebyde; and
c) each of the purified precursors obtained in step (b), after optional protection of the inner nitrogens of the porphyrin ring by magnesium or zinc, is subjected to an alkylation reaction by means of either an allyl halide, or an alkyl tosylate, or an alkyl sulphonate.
The corrole compounds used in the present invention are prepared by the method described in Gross et al., 1999, which comprises solvent-free condensation of pyrrole with the appropriate aldehyde, followed by dehydrogenation and alkylation to obtain the desired salt.
In still another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a tetrapyrrolic macrocycle selected from a novel 5,10,15,20-tetraaryl-porphyrin as defined above and a 5,10,15-triaryl-corrole, wherein said aryl radical of the corrole compound is a carboaryl a heteroaryl or a mixed carboaryl-heteroaryl radical and at least two of said aryl radicals are positively charged. The novel porphyrins are preferably the compounds herein designated P16, P17, P18, P19 and P20, and the corrole is preferably the compound P21.
In a further aspect, the invention relates to a method for inhibiting growth factor receptor tyrosine kinase (RTK) activity comprising the administration of an inhibitor selected from a tetrapyrrolic macrocycle selected from 5,10,15,20tetraaryl-porphyrin and 5,10,15-triaryl-corrole, wherein said aryl radical is a carboaryl, a heteroaryl or a mixed carboaryl-heteroaryl radical and at least two of said aryl radicals are positively charged, in an amount sufficient to inhibit growth factor receptor activity.
The invention further relates to a method for inhibiting angiogenesis comprising the administration of an inhibitor selected from a tetrapyrrolic macrocycle selected from 5,10,15,20-tetraaryl-porphyrin and 5,10,15-triaryl-corrole, wherein said aryl radical is a carboaryl, a heteroaryl or a mixed carboaryl-heteroaryl radical and at least two of said aryl radicals are positively charged, in an amount sufficient to inhibit angiogenesis.
The invention still further relates to a method for prevention of restenosis after percutaneous transluminal coronary angioplasty comprising the administration of an inhibitor selected from a tetrapyrrolic macrocycle selected from 5,10,15,20-tetraaryl-porphyrin and 5,10,15-triaryl-corrole, wherein said aryl radical is a carboaryl, a heteroaryl or a mixed carboaryl-heteroaryl radical and at least two of said aryl radicals are positively charged, in an amount sufficient to inhibit smooth muscle cell proliferation. For this purpose, the selected porphyrin or corrole may be used also in a slow release mode by direct administration into the affected site in the vessel wall or as a chemical conjugate with locally implanted stents.
The invention also relates to a method for inhibiting primary tumor growth and metastasis comprising the administration of an inhibitor selected from a tetrapyrrolic macrocycle selected from 5,10,15,20-tetraaryl-porphyrin and 5,10,15-triaryl-corrole, wherein said aryl radical is a carboaryl, a heteroaryl or a mixed carboaryl-heteroaryl radical and at least two of said aryl radicals are positively charged, in an amount sufficient to inhibit primary tumor growth and metastasis.
The compositions of the present invention can be administered by any suitable mode of administration, e.g. orally or, preferably by injection, e.g. intravenously or subcutaneously, or by conjugation to locally implanted stents. The doses will depend on the condition of the patient and the disorder being treated and can be between 0.1 to 10 mg/kg/day, preferably from 1 to 5 mg/kg/day.